Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID 751658, 17 pages http://dx.doi.org/10.1155/2013/751658

Review Article Updates on Antiobesity Effect of Garcinia Origin (−)-HCA

Li Oon Chuah,1 Wan Yong Ho,2 Boon Kee Beh,3 and Swee Keong Yeap4

1 SchoolofIndustrialTechnology,UniversityScienceMalaysia,11800Penang,Malaysia 2 School of Biomedical Sciences, The University of Nottingham Malaysia Campus, Jalan Broga, 43300 Semenyih, Selangor, Malaysia 3 Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, 43400Serdang,Selangor,Malaysia 4 Institute of Bioscience, University Putra Malaysia, 43300 Serdang, Selangor, Malaysia

Correspondence should be addressed to Swee Keong Yeap; [email protected]

Received 15 June 2013; Accepted 7 July 2013

Academic Editor: Vincenzo De Feo

Copyright © 2013 Li Oon Chuah et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Garcinia is a plant under the family of Clusiaceae that is commonly used as a flavouring agent. Various phytochemicals including flavonoids and organic acid have been identified in this plant. Among all types of organic acids, hydroxycitric acidormore specifically (−)-hydroxycitric acid has been identified as a potential supplement for weight management and as antiobesity agent. Various in vivo studies have contributed to the understanding of the anti-obesity effects of Garcinia/hydroxycitric acid via regulation of serotonin level and glucose uptake. Besides, it also helps to enhance fat oxidation while reducing de novo lipogenesis. However, results from clinical studies showed both negative and positive antiobesity effects of Garcinia/hydroxycitric acid. This review was prepared to summarise the update of chemical constituents, significance of in vivo/clinical anti-obesity effects, and the importance of the current market potential of Garcinia/hydroxycitric acid.

1. Introduction is associated with several chronic and debilitating health problems including hyperlipidemia, hypertension, coronary The world is in health transition. Infection as a major cause heart disease, diabetes, cancer, disease of the gall bladder, of suffering and death is giving way to new epidemics of osteoarthritis, shortage of breath, abnormal dilation of the noncommunicable disorders such as cancer, cardiovascular veins, backache, and even psychological problems [2, 4]. diseases, and diabetes, which continue to plague the world There are a few drugs in the market to ameliorate or at an alarming rate [1]. A trend of increasing prevalence of prevent obesity, but there are costs, efficacy, and side effects obesity and obesity-related comorbidity and mortality was to be considered. For example, the currently available phar- observed over the last few decades [2]. The International macological agents, Sibutramine, Rimonabant, Orlistat, and AssociationoftheStudyofObesity(IASO)reportedonthe Phentermine which are licensed for weight reduction therapy, country rankings in terms of percentage global prevalence of 2 appear to possess some adverse effects5 [ –7]. Phentermine, adult obesity (BMI ≥ 30 kg/m ) in the year of 2012, where for instance, has been reported to cause dry mouth, insomnia, Tonga ranks first with 56.0% obese adults (46.6% of obese headache, dizziness, fatigue, and palpitation [6, 7]. In year male and 70.3% of obese female). In the United States, 2010,FDAhadannouncedthemarketwithdrawalofMeridia IASOreportedthat35.5%ofmenand35.8%womenwere (Sibutramine) due to its risk of serious cardiovascular events obese (BMI ≥ 30) [1, 3]. Overweight and obesity are diag- [6, 7]. Natural products and plant-based dietary supplements nosed zbased on the body mass index (BMI), which is defined have been used by people for centuries. Evidence is starting as quotient of body weight (kg) over the square of stature to emerge to shed light on the consumption of herbs as 2 (m ). According to the World Health Organization (WHO) an effective strategy for disease treatment and health main- standard, overweight subjects are diagnosed with BMI values tenance. Several ethnobotanical studies have reported the in the range of 25–29.99. Obesity itself, defined as BMI ≥ 30, bioprospecting surveys on the positive application of herbs 2 Evidence-Based Complementary and Alternative Medicine

Table 1: Comparison of G. cambogia, G. atroviridis,andG. indica [9, 11, 13, 44].

Species Common name Origin Feature Small- or medium-sized tree with a rounded crown and India: found commonly in the evergreen horizontal or drooping branches, under the family of forests of Western Ghats, from Konkan G. cambogia Asam Gelugor Guttiferae. Its fruits are ovoid, about 5 cm in diameter, yellow southward to Travancore, and in the or red when ripe with six to eight grooves, enclosing six to Shola forests of Nilgiri. eight seeds, and are edible. Small- or medium-sized fruit tree, with drooping branches and ovoid fruits. The fruits are bright orange-yellow when G. atroviridis Asam Gelugor Southeast Asia ripe, globose with 12–16 grooves, about 7–10 cm in diameter, and fluted with a firmly textured outer rind and a rather thin and translucent pulp surrounding the seeds. India: the tropical rain forests of Western Slender evergreen tree with drooping branches. Its fruits are G. indica Kokum Ghats, from Konkan southward to globose or spherical, 2–4 cm in diameter, dark purple when Mysore,Coorg,andWayanad ripe with five to eight large seeds surrounded. in the treatments for obesity [8]. Garcinia has been used slimming aids containing HCA has taken place. The aim of for centuries in Asian countries for culinary purposes as a this review is to critically assess the evidence from a very condiment and flavoring agent in place of tamarind or lemon broad range of reports, rigorous clinical trials, systematic andtomakemealsmorefilling[9, 10]. Besides its use as a reviews, and meta-analyses on the efficacy and potential of flavouring agent, the dried rind of G. cambogia combined Garcinia/HCA as an antiobesity dietary supplement. with salt and other organic acids can help to lower the pH and thus provides a bacteriostatic effect in curing fish. G. cambogia contains large amounts of hydroxycitric acid 2. Uses in Traditional Medical Systems (HCA). Similar to G. cambogia, G. atroviridis and G. indica Botanical dietary supplements usually contain a complex also contain significant HCA content and are sometimes mixture of phytochemicals which have additive or synergistic used interchangeably with G. cambogia in food preparation. interactions. Aside from its use as a preservative and as a The different features among these three different types of condiment in cuisine, Garcinia extracthasbeenusedinthe Garcinia are summarised in Table 1 [9, 11–14]. traditional Ayurvedic medical system [9, 13]. A decoction of AmyriadofhealtheffectshavebeenattributedtoGarci- G. cambogia is given as purgative in the treatment of intestinal nia (including G.cambogia,G.atroviridis,andG. indica), worms and other parasites, for bilious digestive conditions, such as antiobesity effects [15–17], antiulcerogenic [18–20], for dysentery, rheumatism, and in the treatment of tumours. antioxidative [21–24], antidiabetes [25], antimicrobial [22, Less commonly, extracts are employed as cardiotonics to treat 26–28], antifungal [29], anti-inflammatory [30, 31], and angina. In veterinary medicine, it is used as a rinse for diseases anticancer effects22 [ , 32–34]. In particular, the antiobesity of the mouth in cattle [12, 77]. The fruit rind is used in rickets effects of Garcinia or more specifically of its HCA content and enlargement of spleen and to heal bone fractures [13]. In have been elucidated with unprecedented clarity over the last Southeast Asian folkloric medicine, a decoction of G. atro- few decades. Besides its efficacy in the reduction of body viridis (leaves and roots) is sometimes used for the treatment weight and food intake, Garcinia/HCA has been proven to of cough, dandruff, earache, stomach pains associated with be beneficial in ameliorating obesity-related complications pregnancy, and throat irritation [49]. The dried fruit of G. such as inflammation, oxidative stress, and insulin resistance atroviridis is used for improving blood circulation, for the [21]. The results obtained from several studies supported the treatment of coughs, as a laxative, and as a expectorant. The positive effects of HCA administration alone or in combina- fruit is used in a lotion with vinegar to rub over the abdomen tion with other ingredients on body weight loss, reduced food of women after confinement [9]. Fruit of G. indica is antiscor- intake, increased fat oxidation, or energy expenditure (EE) butic, cholagogue, cooling, antibilious, emollient, and demul- [16, 17, 35–39] whereas some studies did not [40–42]. cent. The anthelmintic properties of the fruit of G. indica In spite of the vastly reported prominent role of HCA contributedtoitsuseinhaemorrhoids,dysentery,tumor, in inducing satiety, reduced energy intake and weight gain, pains, and heart complaints. Bilious affected sites are treated and improved blood parameters and substrate oxidation, with syrup from the fruit juice. Kokum butter is astringent controversial results regarding its efficacy and safety as and demulcent and is used in diarrhea and dysentery. It is also an antiobesity dietary supplement had also been reported. applied externally for ulcerations, sinuses, fissures of hand, Evidence from the in vitro, in vivo, and clinical trials on lip, chapped skin, and skin diseases [12, 13, 44, 77]. the safety of Garcinia/HCA as a dietary supplement for treating obesity had been extensively reviewed [43]. However, the efficacy of Garcinia/HCA remains the subject of debate. 3. Phytoconstituents Despite the previously stated issues, on conclusive evidence for HCA’s efficacy in promoting weight loss and suppressing The several compounds which have been isolated from food intake, the marketing of a plethora of over-the-counter various species of Garcinia aresummarisedinTable 2.Several Evidence-Based Complementary and Alternative Medicine 3

Table 2: Phytochemicals of Garcinia.

Phytochemicals G. cambogia G. indica G. atroviridis Organic acids (−)-HCA Fruit rind [45, 46]Fruitrind[45]Fruitrind[45] Leave and fruit rind Herbal products Citric acid Fruit rind [46] [47] [48] Herbal products Tartaric acid [46]nd [47]nd [48] Herbal products Malic acid Fruit rind [46][47]nd [48] Succinic acid — [47]nd — Prenylated benzoquinone Atrovirinone — — Root [27] Prenylated depsidone Atrovirisidone — — Root [27] Atrovirisidone B — — Root [49] Prenylated hydroquinone 4-Methylhydroatrovirinone — — Root [50] 1,4-cis-Docosenoic acid — — Root [50] 14-cis-Docosenoic acid — — Root [50] Flavonoid Morelloflavone — — Root [50] Fukugiside — — Root [50] Naringenin Root [49] 󸀠󸀠 3,8 -Binaringenin Root [49] Xanthone Garbogiol Root [51]— — Rheediaxanthone A Bark [51]— — Dioxygenated xanthone 1,7-Dihydroxyxanthone — Heartwood [52]— Tetraoxygenated xanthone Atroviridin — — Stem bark [53] Tetracyclic xanthone Oxyguttiferone K Fruit [54]— — Polyisoprenylated benzophenone Fruit rinds [55, 56] [55]nd Garcinol/camboginol (enantiomer of xanthochymol) — Latex [57] Fruit rinds [58] Bark [51] Latex [57] Isogarcinol/cambogin (enantiomer of isoxanthohumol ) Fruit rinds [58]— Bark [51] Isoxanthohumol Fruit rinds [55][55]nd — Guttiferone I Fruit [54]— Guttiferone J Fruit [54]— Guttiferone K Fruit [54]— Guttiferone M Fruit [54]— Guttiferone N Fruit [54]— nd: none detected; —: not reported. 4 Evidence-Based Complementary and Alternative Medicine

HO O O OHO OH HO OH Garcinia/HCA Insulin, leptin EE -workout (YES); D resting ?? Glucose intake and RER (YES); RQ ?? Citrate to oxaloacetate and acetyl-CoA B De novo lipogenesis Glycogen Carbohydrate synthesis oxidation Fatty acid and cholesterol biosynthesis

Fatty acids supply Food intake suppression ∗ affecting adipose conversion Serotonin A Serotonin regulation C Fat oxidation Weight management Antiobesity Appetite

Figure 1: Possible multiple mechanisms that contribute to antiobesity effect of Garcinia/HCA. ↑ indicated increase or stimulation; ↓ indicated reduce or inhibition while ?? indicated that the effect is yet to be confirmed. (A) summary of Serotonin regulation and food intake suppression; (B) summary of reduction of de novo lipogenesis; (C) summary of stimulation on fat oxidation; (D) summary of reduce on glucose intake; (A) and (B) contribute to the weight management effect of Garcinia/HCA while (B) and (C) contribute to antiobesity of Garcinia/HCA.

types of organic acids such as HCA, citric, tartaric, malic, 4. Salts of HCA andsuccinicacidsareisolatedfromGarcinia.However, − HCA is the principal acid of the fruit rinds of G. cambogia, Onaccounttothediscoveryof()-HCA as an effective G. indica, and G. atroviridis [12, 27, 45], with its content compound in weight management, market demand for the ascending as listed [46–48]. A substantial amount of (−)- acid has increased tremendously. The commercially available − HCA, up to 30% by weight is present in the pericarp G. cambogia extracts which contain approximately 50% ( )- of the fruit of G. cambogia. In similar studies conducted HCA are prepared from the fruit rind [12, 69]. HCA can exist by Sullivan et al. [78, 79]andStallingsetal.[80], they as a free acid or in the lactone form. The former form is observed that of the four isomers of HCA [(–)-HCA, (+)- considered to be biologically active. However, the free acid HCA, (–)-allo-HCA, and (+)-allo-HCA], (−)-HCA, which is is unstable and is usually converted to its less active lactone also known as (2S, 3S)-HCA, was the only potent inhibitor form to attain higher stability. To prevent the cyclization of of ATP citrate lyase. (−)-HCA can be chemically synthe- HCA into its less potent lactone, the acid has been combined sized using citric acid as starting material. Synthetic (−)- with various counter ions to form stable salts [83]. HCA offers several advantages including higher purity and Commercial HCA is available in free acid form and as lactone stable as compared to natural (−)-HCA [81]. On single, double, or triple salts. Preparations with different − counter ions contribute to different degree of solubility as the other hand, ( )-HCA is a good starting material to + synthesize other important chiral synthons and compounds well as bioavailability [84]. For example, Na salt of HCA had beenshowntobemoreeffectivethanitslactoneininhibiting [82]. + (−)-HCA is one of the important supplements for anti- lipogenesis. However, Na salt is highly hygroscopic when − obesity and weight management. Its effect on weight man- bound to ( )-HCA, which would deemed unfavorable for the agement is mainly contributed by giving the feeling of full production of pharmaceuticals for dry delivery [85]. and satisfaction while the antiobesity effect is by reduction To address the need to achieve higher solubility and of de novo lipogenesis and acceleration of fat oxidation stability, recent approaches have been focused more on the (Figure 1). In this paper, we aimed to review the mechanism preparation of (−)-HCAintheformofadoubleortriple for antiobesity and weight management effects by− ( )-HCA salt. Similar to its single salts, these double or triple salts also (hereafter referred to as HCA)/G. cambogia/G. atroviridis/G. serve as good supply for essential ions [84]. A remarkable 2+ + indica extracts and the assessment of these effects in the example of these would be the Ca /K salt of (−)-HCA clinical settings. (HCA-SX) or Super CitriMax. In contrast to the single salts, Evidence-Based Complementary and Alternative Medicine 5

HCA-SX is completely soluble in water and thus confers effects of G. cambogia/HCA resulted from the combined higher bioavailability [84]. A number of studies on the safety actions of several mechanisms including suppressing de novo of HCA-SX had been reported [43]. Daily intake of HCA- fatty acid biosynthesis and appetite [16, 60] and increasing SX at this dosage was shown to be effective in reducing energy expenditure [39], subsequently reducing body fat body weight and BMI of healthy and obese adults after accumulation and weight gain in experimental animals [37, clinical trials of 8 weeks [16, 64]. Gene expression studies 38, 92]. In this review, we arranged the antiobesity effects of also provided additional evidence for the safety of HCA-SX, Garcinia/HCAbasedontheirdistinctmechanisms:(1)sero- where genes essential for mitochondrial/nuclear proteins and tonin regulation and food intake suppression, (2) decreased for fundamental support of adipose tissue were shown to be de novo lipogenesis, (3) increased fat oxidation, and (4) independent of the regulation by HCA-SX [17, 86]. downregulation of a spectrum of obesity-associated genes. A typical reduction of food appetite and an increased serotonin availability were observed in all the weight control 5.1. Serotonin (5-Hydroxytryptamine, 5-HT) Regulation and studies of HCA-SX on both animal and human subjects. Food Intake Suppression. HCA, the primary acid in the fruit These were associated with reduced levels of total cholesterol, rinds of G. cambogia, G. atroviridis,andG. indica [45], has LDL, triglycerides, and serum leptin as well as increased been reported as the active ingredient in inhibiting ATP HDL level and urinary excretion of fat metabolites [15, 16, citrate lyase (EC 4.1.3.8) [78, 93]. ATP citrate lyase, which 64, 84, 87]. In rats, the salt also caused downregulation of is an extramitochondrial enzyme catalyzing the cleavage of genes encoding abdominal fat leptin while expressions of the citrate to oxaloacetate and acetyl-CoA, was inhibited by plasma leptin genes remained unaltered [17]. Nevertheless, it HCA. Thus, the availability of two-carbon units required for was postulated that a set of obesity regulatory genes [84]and the initial steps of fatty acid and cholesterol biosynthesis 3 inhibition to the uptake of [ H]-5-HT release in the brain [15] during carbohydrate feeding was limited [78, 79, 94–97]. As a areinvolvedintheappetitesuppressingactivityofHCA-SX. result, the consumed carbon source was diverted to glycogen In relation to this, gene expression profiling carried synthesis in liver. A signal was then sent to the brain due to out by a research group demonstrated the modulation of this metabolic alteration, resulting in rising of serotonin level a specific set of genes (about 1% of 9960 genes and ESTs) concomitant with a reduced appetite. HCA might exhibite in the adipocytes by dietary HCA-SX supplementation [17]. its anorectic effect by a second possible mechanism, namely, Further study on cultured mature human adipocytes revealed reducing acetyl CoA, subsequently decreasing malonyl CoA significant upregulation of 366 and downregulation of 348 levels and thereby reducing negative feedback on carnitine the fat- and obesity-related genes [88]. Notably also in the acyltransferase (CPT-1). The substrate of CPT-1, long-chain microarray analyses, HCA-SX demonstrated a distinct effect acyl CoA(s), may act as a mediator(s) of appetite [98, on appetite suppression whereby genes encoding serotonin 99]. More recently, neuropeptide Y (NPY) had also been receptors were shown to be selectively upregulated by the implicated in the appetite suppression of HCA. Basal concen- salt [17]. Besides, HCA-SX was also found to be capable tration of the neurotransmitter was claimed to be significantly of activating hypoxia inducible factor (HIF), a transcription reduced in the hypothalamic tissues as a result of supplemen- factor involved in energy metabolism [88]andrestored tation with HCA-SX [84]. However, the role of NPY in this the increase in oxidative stress, inflammation, and insulin is still vague to date. Several reports supported the serotonin resistance in obese Zucker rats [21]. regulation of HCA. Ohia et al. [100] demonstrated that HCA- SX enhanced serotonin availability in isolated rat brain cortex 5. Antiobesity Effects of Garcinia/HCA by acting as a mild serotonin receptor reuptake inhibitor (SRRI), without stimulating the central nervous system. Kaur Obesity, particularly caused by accumulation of visceral fat, is and Kulkarni [36] conducted a study to elucidate the effect a serious risk factor of various life-style diseases such as coro- of OB-200G, a polyherbal preparation containing aqueous nary heart disease, diabetes, hyperlipidemia, hypertension, extracts of G. cambogia, Gymnema sylvestre, Zingiber offici- and cancer [2, 4]. Human obesity is influenced by genetic nale, Piper longum, and resin from Commiphora mukul on the and environmental factors and particularly by changes in diet modulation of food intake by serotonin modulators in female and physical activity, which contributes greatly to the devel- mice. The results obtained were compared with fluoxetine, a opment of insulin resistance, a most common underlying drug that was reported to enhance 5-HT neurotransmission abnormality in human obesity [89]. Studies on food sources [101]. Both OB-200G and fluoxetine significantly (𝑃 < 0.05) exerting antiobesity effects have focused on the development antagonized the hyperphagic effect of p-chlorophenylalanine of herbal extracts or functional food which can suppress the (PCPA), 8-hydroxy-2-(di-N-propylamino)-Tetralin (8-OH- accumulation of body fat. Several studies were conducted to DPAT), cyproheptadine, and 2-deoxy-D-glucose (2-DG) provide scientific basis on the extensive usage of G. cambogia which further instigate possible serotonergic involvement in and G. atroviridis associated with high-fat diet- (HFD- the effects of OB-200G on food intake in female mice. Preuss ) induced obesity where dyslipidemia, fatty liver, insulin et al. [16]reportedthatHCAcausedasignificantreduction resistance, and hyperleptinemia were acquired along with the in appetite, weight loss, and plasma leptin level, concomitant overexpression of leptin, TNF-𝛼,resistin,PPAR𝛾2, C/EBP𝛼, with an increase in the serum serotonin level and a favorable and SREBP1c genes in epididymal adipose tissue. The effect lipid profile in human clinical trials. Similar results were also of G. cambogia waslargelyattributedtoitsHCAcontent obtained in a study conducted by Asghar et al. [87]They [90, 91]. Subsequent researches proved that the antiobesity reported on increased brain serotonin level in obese Zucker 6 Evidence-Based Complementary and Alternative Medicine rats receiving G. cambogia extract, suggesting that the ability experiments elucidating the effects of HCA in combination of HCA in body weight gain reduction was most probably with the 12% fat diet on meal size and meal number during due to its combined effects on the metabolic and serotonin the light phase revealed that HCA markedly reduced the pathways. In addition, Roy et al. [17]reportedthatHCA- meal number, but not the meal size. HCA did not affect SX supplementation upregulated prostaglandin D synthase any metabolic variables tested (plasma glucose, lactate, tri- (PDS), aldolase B (AldB), and lipocalin (LCN2) genes in acylglycerol,HDL,freefattyacids,𝛽-hydroxybutyrate, and abdominal fat tissue. Further mapping of the candidate genes insulin, hepatic fact, and glycogen concentrations) in both of known pathways associated with fat metabolism by using experiments, except decreasing plasma triacylglycerol levels functional categorization and pathway construction software and increasing the liver fat concentration in Experiment 2 showed that supplementation of HCA-SX targeted on the (rats fed with 12% fat diet). The fact that HCA did not affect serotonin receptor. plasma 𝛽-hydroxybutyrate (BHB) levels did not support the Leonhardt et al. [102]reportedthatHCAreducedbody hypothesis that HCA suppressed food intake via increased weight regain in rats after a period of substantial body hepatic fatty acid oxidation. weight loss. Besides, HCA temporarily reduced food intake However, contradicting results were obtained by Kovacs of rats with diets of varying nutrient contents (grounded et al. [41, 71] who reported that two-week supplementation standard rat chow, high glucose, and high glucose + fat). with HCA and HCA combined with medium-chain triglyc- HCA supplementation caused pronounce suppression of erides did not result in increased satiety. The findings were food intake during the entire 10 days of ad libitum feeding in line with previous reports where no significant treatment period in rats fed with high glucose + fat diet, a diet that had effects were observed on appetite indices (inclusive of mean, anutritionallyrelevantlevelofdietaryfat(24%ofenergy). peak or nadir hunger ratings, mean ratings of desire to eat, These data therefore extended those of the previous studies prospective consumption, fullness or sensations of thirst, whichreportedontheanorecticeffectsofHCA[96, 97, 103– stomach growling, headache, distraction, irritability, or, as a 105]. Moreover, the results obtained were consistent with check on malingering, itchiness) [69]. The lack of efficacy and studies which reported on particularly strong food intake transient food intake suppression by HCA raised questions suppression by HCA with high glucose + fat diet and a smaller about its clinical significance. While negative findings are but still significant suppression with the high glucose diet in always open to methodological questions, several questions other rat models and in different orders37 [ , 39, 102]. Hence, need to be answered before drawing a definite conclusion. the feed conversion efficiency [cumulative body weight regain First, the diet administered to the subjects should not (g)/cumulative food intake (MJ)] in the high glucose and promote extreme sensations in the evaluation of the food high glucose + fat groups during the 10 ad libitum days intake suppression effects of HCA under conditions of energy was reduced, which indirectly supported that HCA increased restriction. However, Mattes and Bormann imposed mild energy expenditure in these groups. restrictionsandthusruledoutthispossibilityasevidenced Leonhardt and Langhans [39] then extended their study by ratings falling in the middle range of the response on the long-term effects of HCA on body weight regain and scales. Second, an energy-restricted diet would prevent the food intake, as well as the effects of HCA on the circadian required enzyme alterations (reduction of acetyl-CoA and distribution of food intake and on meal patterns during suppression of formation of carnitine palmitoyltransferase I the dark and light phases. HCA administration significantly inhibitor malonyl CoA) which altered substrate metabolism reduced the food intake of rats fed with 12% fat diet, but and satiety. However, it was unlikely that the moderate energy not 1% fat diet, concomitant with significant reduction in restricted diet prescribed in the study conducted by Mattes weight regain (overall 𝑃 < 0.01)inbothgroups.Inthestudy, and Bormann [69] hindered the satiety effect of HCA as it the rats underwent restrictive feeding for 10 days prior to still contained at least 30% of energy from fat. ad libitum feeding (Experiment 1: normal 1% fat diet and Several factors might contribute to the controversial 1% fat diet + 3% HCA; Experiment 2: normal 12% fat diet results of the efficacy of HCA in human studies. One of and 12% fat diet + 3% HCA). The control groups of both contributingfactorsisthehighlyvariabledosesusedinthe experiments had compensated the body weight loss, whereas human trials which ranged from 5 to 250 mg/kg of HCA the HCA-fed rats groups regained only 68 ± 4% (1% fat diet) per day [42, 70]. Besides, the discrepancy might also be and 61 ± 8% (12% fat diet) of the body weight regained by due to the differences in the preparation or extraction of their respective control groups after 22 days of such ad libitum HCA. For instance, the extraction method might increase the feeding. Despite significant reduction in weight regain in formation of HCA in a lactone form, which is less potent rats fed with 1% and 12% fat diet, long-term suppression in the inhibition of ATP citrate lyase [85, 107]. In order to of HCA on food intake was only detected in combination prevent the cyclization of HCA into the less potent lactone with 12% fat diet (Experiment 2). This was in line with the form, preparation using different counte rions (such as results obtained by Leonhardt et al. [106]whosuggestedthat potassium, sodium, or calcium) had been applied [84], which HCA increased energy expenditure. Studies on the effects of contributed to the different degrees of stability, bioavailability, HCA on the circadian distribution of food intake and on or solubility of HCA [86]. In this respect, Louter-Van De Haar meal patterns showed that the suppression of food intake et al. [83]conductedastudyontheefficacyofthreecommer- occurred predominantly during the dark phase of the first cially available HCA products on suppression of food intake ad libitum days. However later on, HCA suppression of food in male Wistar rats. Many human studies which reported intake was more effective during the light phase. Further lack of efficacy used Super CitriMax at considerably lower Evidence-Based Complementary and Alternative Medicine 7 doses [41, 70, 71]. On the contrary, Preuss et al. [16]reported Subsequently, a 7-day high-carbohydrate diet (F/CHO/P, that high doses of Super CitriMax exerted significant effects <5/>85/10% energy; 130–175% of EE; overfeeding period) in human. Thus, Louter-Van De Haar et al. [83]suggested supplemented with either 500 mg of regulator HCA (HOB that the reported lack of efficacy of HCA in suppressing food Ireland Ltd.) or placebo was administered. Each intervention intake in human subjects might be due to the low doses ended with a 60 h stay in the respiratory chamber (days 9 and of a relatively low-effective HCA preparation. Nevertheless, 10). De novo lipogenesis occurred as indicated by RQ > 1.00 in significant suppression of food intake was observed in the all subjects. Significantly, lower 24 h EE𝑃 ( < 0.05;onday9), studies conducted by Leonhardt and Langhans [39]where resting metabolic rate (𝑃 < 0.01;onday10),andRQatnight Sprague-Dawley rats were supplemented with HCA for 10 (𝑃 < 0.05; on day 10) were detected with HCA as compared days after substantial, fasting-induced weight loss. It seemed to placebo. Fat balance and thus net fat synthesis as de novo that HCA might be more effective in regulating weight gain lipogenesis tended to be lower (𝑃 < 0.1)withHCAascom- than promoting weight loss; thus it was more useful for weight pared to placebo. Taken all together, Kovacs and Westerterp- maintenance after an initial loss [39, 102]. Hence, differences Plantenga concluded that the administration of HCA during in the experimental setups such as the difference in rat strains overfeeding of carbohydrates may reduce de novo lipogenesis. could contribute to such discrepancy. However, opinions differ widely with respect to this issue. The mechanism underlying the anorectic effect of HCA is 5.2. Decreased De Novo Lipogenesis. The reduction of the still unclear. Furthermore, whether the suppression of body acetyl-CoA by HCA and thus limiting the availability of weight regained was solely due to reduced food intake or building blocks required for fatty acid and cholesterol biosyn- whether there was involvement of increased EE remained thesis has led to suggestions that HCA inhibited lipogenesis. unknown. Contradictory results were reported on the effects Several studies conducted by Sullivan and colleagues had of HCA on EE. Previous reports by Leonhardt and colleagues confirmed the inhibition of in vivo and in vitro rates of lipoge- [39, 102] and the results obtained in pair-feeding studies nesis in several tissues reported to convert carbohydrate into [103] showed reduction of body weight regain and energy fatty acids (such as liver, adipose tissue, and small intestine), conversion ratio by HCA supporting the finding that HCA in which HCA was predominantly given to rodent models increased EE. However, reduced energy conversion ratio [78, 79, 85, 96, 97, 108]. Lowenstein [108] demonstrated that could be due to decreased nutrient absorption. Vasselli et al. HCA greatly inhibited in vivo fatty acid synthesis in rat liver. [111] demonstrated an increment in 24 h EE in rats fed with The rats were placed on chow diet for 7–10 days, followed by mixedhigh-carbohydratedietadlibitumbydirectlymeasur- 45 h of fasting prior to a scheduled diet high in fructose or ing the EE in a whole-body respirometer, albeit no effect on glucose for 10 to 15 days. The sodium salt of HCA at dose levels the RQ was detected. Another study conducted by Leray et of 2 to 20 mM was administered by intraperitoneal injections al. [112] reported that 6 months of HCA administration did 3 45 min before injection of H2O. Fatty acid biosynthesis in not affected EE in adult neutered cats. Besides, most human 3 rat liver (𝜇 moles H2O incorporated/g liver/h) was measured studies [41, 42, 70] reported that HCA had no effect on EE. 3.5–5 h after starting of the final feeding. Profound decrease Kriketos et al. [42] reported that HCA administration exhib- in fatty acid synthesis by 25 to 30 days was obtained with ited no effect on lipid oxidation in men during either rest or an intraperitoneal dose of 0.1 mmole per kg of body weight moderately intense exercise on a cycle ergometer. However, (equivalent to approximately 2.9 mg of HCA per 150 g rat). In in these studies, the subjects received a much smaller dose, addition, 50% of inhibition was detected at a dose level of 0.28 namely, a daily dose of 3.0 g per subject [nearly equal to mmole per kg body weight. 1.5 mg/day/mouse]. Furthermore, their experimental period It was reported that G. cambogia/HCA affected respira- of 3 days was quite short when compared with other studies. tory quotient (RQ) and EE in rats and human. Lim et al. Blunden [113]reportedthatwhenGarcinia extract and [109, 110] showed that short-term administration of HCA insulin were added simultaneously, the number of larger decreased the RQ in athletes and in untrained women. Leon- droplets markedly decreased while the smaller droplets (10– 2 2 hardt et al. [106] further extended their study to determine 20 𝜇m or <10 𝜇m ) increased in 3T3-L1 cell. The activity the effect of HCA on RQ and EE in rats fed ad libitum after of cytosolic glycerophosphate dehydrogenase (GPDH) which a period of substantial weight loss. They reported that HCA converts dihydroxyacetne phosphate to glycerol 3-phosphate markedly decreased RQ and EE during the first two days of ad (predominant substrate for triglyceride synthesis) increased libitum, reflecting suppression of de novo lipogenesis in rats, from undetectable levels to between 100 and 187 U/mg of which is consistent with the findings of Westerterp-Plantenga cytosolic protein after adipose conversion. However, no and Kovacs [61]inhumans. significant decrease in enzymatic activity was detected after In this respect, Kovacs and Westerterp-Plantenga [60] administration of the Garcinia extract. Taken together, the further extended their study where the effects of HCA authors therefore suggested that Garcinia extract interferes on net fat synthesis as de novo lipogenesis were investi- with lipid synthesis in fat cells via fatty acid supply inhibition gated. A double-blind, placebo-controlled, randomized, and without affecting adipose conversion. crossover design experiment was conducted on 10 sedentary male subjects. The subjects performed glycogen depletion 5.3. Increased Fat Oxidation. Ishihara et al. [35]conducted exercise, followed by a 3-day high-fat low-carbohydrate a study on acute and chronic effects of HCA on energy (F/CHO/P, 60/25/15% energy; 100% of EE; depletion period) metabolism. Acute administration of 10 mg/100 𝜇Lofa intake in order to create a similar glycogen storage capacity. 0.48 mol/L HCA solution per mice significantly increased 8 Evidence-Based Complementary and Alternative Medicine

(𝑃 < 0.05) serum free fatty acid levels and concentration of combination with NBC and GSE, could effectively promote glycogen in the gastrocnemius muscle, even though the breakdown of fats [16, 64]. respiratory exchange ratio was not different from that in the control group. On the other hand, chronic adminis- 5.4. Downregulation of a Spectrum of Obesity-Associated tration of 10 mg HCA twice a day significantly lowered Genes. Lipogenic transcription factors, including SREBP1c, (𝑃 < 0.01) the RQ during resting and exercising conditions liver X receptors, PPAR𝛾,andC/EBP𝛼, are highly expressed in mice. Lipid oxidation, calculated from RQ, and oxygen in the adipose tissue and actively participate in the lipid consumption were significantly enhanced, and carbohydrate metabolism of adipocytes by coordinating lipogenic and oxidation was significantly less in these mice during the adipocyte-specific gene expression114 [ ]. PPAR𝛾 interacts early stages of running (𝑃 < 0.01). Taken all together, the with several other transcription factors. C/EBP𝛼 and PPAR𝛾 authors therefore suggested that chronic administration of interact via a positive feedback loop in the differentiated HCA augmented the endurance exercise performance in adipocytes, to induce each other’s expression [115]. Besides, mice via the attenuation of glycogen consumption caused by coexpression of PPAR𝛾 with SREBP1c increases the transcrip- the promotion of lipid oxidation during running exercise. tional activity of PPAR𝛾 [116]. aP2 (a marker of terminal Furthermore, Ishihara et al. [35]suggestedthatchronicHCA adipocyte differentiation), together with several adipocyte- administration might have increased EE during the 3-week specific genes, including adiponectin, insulin receptor, leptin, experimental period. glucose transporter 4 (GLUT4), and glycerol phosphate In addition, Lim et al. [109, 110] also showed that short- dehydrogenase, are induced during the adipogenic differ- term administration of HCA increased fat oxidation during entiation process [114]. Leptin, a 167-amino acid hormone exercise in athletes and in untrained women. Lim et al. [110] and a biomarker of the obesity regulatory gene, is produced conducted a randomized, placebo-controlled study where by fat tissue and is known to regulate energy intake and subjects (athletes) consumed HCA (250 mg) or placebo for metabolism. Leptin binds to the medial nucleus of the 5 days, after each time performing cycle ergometer exercise hypothalamus and induces a sensation of satiety and thus at 60% VO2 maxfor60minfollowedby80%VO2 max until controlling the appetite [98, 117, 118]. exhaustion. The results obtained showed that the respiratory Fatty acid synthase, acetyl-CoA carboxylase 1, and exchange ratio (RER) was significantly lower in the HCA trial SREBP1c mRNA concentrations were decreased in the adi- than in the control trial (𝑃 < 0.05). Fat oxidation was sig- pose tissue of the obese animal models [119]. On the con- nificantly increased by short-term administration of HCA, trary, the mRNA and protein expression of TNF𝛼 (which and carbohydrate oxidation was significantly decreased (𝑃< is involved in proinflammation, apoptosis, lipid metabolism, 0.05) during exercise in athletes. In a continuation of their andinsulinresistance)wereincreasedintheadiposetissues study, Lim et al. [109]conductedasimilarstudytoevaluate of the obese rodents and humans [120]. A high level of TNF𝛼 the effects of HCA administration on fat oxidation during suppressed transcription factors such as PPAR𝛾 and C/EBP𝛼 exercise in untrained women. The results showed that HCA which, in turn, activated the GLUT4 gene [121, 122]. decreased the RER and carbohydrate oxidation during 1 hour Hayamizu et al. [123]evaluatedtheeffectsofG. cambogia of exercise. In addition, exercise time to exhaustion was fruit rind extract containing 60% (–)-HCA on serum leptin significantly enhanced𝑃 ( < 0.05). and insulin in mice. G. cambogia extract reduced serum total A more recent approach for determining fat metabolism cholesterol, triacylglycerol, and nonesterified fatty acids in by HCA was conducted by measuring urinary concentration mice. Nevertheless, the body weight gain and fat pad weight of malondialdehyde (MDA), acetaldehyde (ACT), formalde- were not affected in the treatment. No significant difference hyde (FA), and acetone (ACON) of the tested subjects. The in blood glucose level was detected between groups, but a sig- urinary excretion of these four metabolites was proposed nificant reduction of serum insulin (𝑃 < 0.05) was detected, to be a consequence of enhanced 𝛽-oxidation of fats in suggesting that the G. cambogia extract efficiently improved body tissues [16]. The effect of HCA-SX had been studied glucose metabolism in the treated animals. In addition, the extensively by Preuss et al. on obese human subjects [16, 64] treatment decreased serum leptin levels and the leptin/WAT as well as on male and female Sprague-Dawley rats. In the ratio. Besides, the changed ratio of body weight correlated randomized, double-blind, and placebo-controlled clinical positively with leptin levels in their study. Furthermore, it had studies on obese human, a group of subjects were given been reported that leptin suppressed the signal transduction 4,667 mg of HCA-SX daily (provided 2,800 mg HCA/day) of insulin via cytokine interactions [124, 125]. Hayamizu et al. while the other given a combination of HCA-SX 4,667 mg, [123] suggested that the observed effect of G. cambogia extract 4 mg of niacin-bound chromium (NBC), and 400 mg of on serum insulin in their study occurred through leptin-like gymnema sylvestre extract (GSE) daily. The control group activity. received placebo in 3 equal doses daily at 30 to 60 min before The antiobesity effects of Garcinia on visceral fat mass, meals. In the trial involving 30 subjects, urinary excretion lipid profiles in the serum and liver, serum adipocytokine of fat metabolites was increased by approximately 125–258% levels, and regulation of the expression of multiple adipose whereas in trial involving 60 and 90 obese subjects, the tissue genes were reviewed. Kim et al. [37]reportedthe metabolite excretion increased by about 35.6–106.4% [16]and antiobesity effects of a mixture composed of aqueous extract 32–109% [64], respectively. As excretion of fat metabolites of G. cambogia, soypeptide,andL-carnitine(1.2:0.3:0.02, was enhanced in groups receiving the combination formula, w/w/w) on rats rendered obese by high-fat diet (HFD). it was also suggested that HCS-SX, either alone or in An HFD (40% fat calories) with identical composition of Evidence-Based Complementary and Alternative Medicine 9

Table 3: Summary of clinical studies of Garcinia/HCA that have shown significant antiobesity effect.

Duration Subject Treatment Outcome References 4 g for the 1st day followed by 3 g 10 days 44 healthy volunteers Not recorded [59] until day 10. No significant effects on body weight gain, appetite-related, and plasma Normal, groups: placebo, HCA parameters but decreased fat deposition 11 days of total 10 sedentary male under 1500 mg HCA daily ∗∗ [60] Comments: suggest that (−)-HCA may high-fat diet reduce net fat deposition from de novo lipogenesis during weight gain BMI 27.5, groups: placebo, HCA Reduced of energy intake and slight 2weeks of 24 subjects each (12 males, 12 300 mg HCA [61] decreased of body weight females) Obese, hypocaloric diet, groups: 55 mg Gcambogia+19mg Weightlossassociatedwithlower 4weeks placebo, 1 capsule, 2 capsule, (50 chromium + 240 mg [62] TC/LDL and higher HDL subjects each group) chitosan/day BMI 25–35, groups: placebo, Reduced of visceral and subcutaneous fat 8weeks 1000 mg HCA/day [63] treatment of 20 each area Significant𝑃 ( < 0.05) decrease in BMI, food intake, total cholesterol, low-density lipoproteins, triglycerides, and serum HCA-SX 4667 mg (60% HCA), leptin levels, increase in high-density Moderate obese, groups: placebo, 4667 mg HCA-SX + 400 𝜇g lipoprotein levels, and enhanced 8weeks HCA-SX, HCA-SX + NBC + GSE niacin-bound chromium + [16] excretion of urinary fat metabolites of total 60 400 mg Gymnema sylvestre (biomarker of fat oxidation, including extract malondialdehyde, acetaldehyde, formaldehyde, and acetone) in HCA and HCA-NBC-GSE groups BMI 30–50, groups: placebo, 2800 mg HCA; 2800 mg of 2800 mg HCA; 2800 mg HCA + Decreased of body weight, BMI, LDL, 8weeks HCA-SX + 400 𝜇gchromium+ [64] 400 𝜇g chromium of 30 subjects and TG and increased fat oxidation 100 mg gymnemic acid/day each Normal, group: 35 healthy Significant reduction of total cholesterol, 1500 mg G. cambogia extract 8weeks subjects on diets 1000, 1200, or triacylglycerol, and body weight [65] daily 1500 kcal associated with reduced appetite Significant reduction of body weight, BMI, body fat, lean body mass, and anthropometric parameters (biceps, Obese, groups: placebo and 8weeks 3.45 g G. atroviridis subscapular, suprailiac crest skinfold [66] treatment of total 50 F thicknesses, and upper arm circumference) but no change of serum lipid profile Over weight to obese, groups: 285 mg (−)-HCA in Slim339 G. 60 days Significant reduced of body weight (4.7%)67 [ ] placeboandtreatmentoftotal58 cambogia extract daily BMI 27.5–39, groups: placebo 300 mg G. cambogia +1200mg Significant body weight lost (3.5 kg versus 12 weeks and treatment (18 females/2 Phaseolus vulgaris +1200mg [68] 1.2 kg) males each) of total 40 inulin/day BMI ∼28, groups: placebo: 47; 12 weeks 2400 mg G. cambogia/day Significant body weight lost [69] treatment: 42 the high-fat control diet (CD) applied in the study was fed rats. Moreover, the mixture of G. cambogia,soypeptide,and to five-week-old male Sprague-Dawley rats for 9 weeks to L-carnitine improved dyslipidemia in rat models with HFD- create an obese conditions in rats that mimic to human induced obesity. Downregulation of the expression of leptin, obesity. Body weight gain, visceral fat-pad weight, and serum tumor necrosis factor-alpha, and sterol regulatory element and hepatic biochemistry of rats were measured. The 0.38% binding protein 1c genes in the epididymal fat tissue of rats fed mixture-supplemented HFD (D + M) reduced the total with CD + M diet was obtained. In contrary, upregulation of body weight and the accumulation of visceral fat mass and the uncoupling protein 2 (UCP2) gene in epididymal adipose loweredthebloodandhepaticlipidlevels,whichledtothe tissues was induced with CD + M diet. No effect on the food improvement of insulin resistance in the HFD-induced obese intake of the animals was observed in the study, suggesting 10 Evidence-Based Complementary and Alternative Medicine

Table 4: Summary of clinical studies of Garcinia/HCA that have shown none significant antiobesity effect.

Duration Subject Treatment Outcome References Normal, groups: placebo, HCA No significant changes in total fat and 1day 4300 g HCA [70] of total 10 cyclists carbohydrate oxidation rates No significant differences in satiety, daily energy intake and body weight loss within all groups ∗∗ Normal-moderately obese, Comment: subjects were under 500 mg HCA; 500 mg HCA + 3 g group: placebo, HCA, and HCA negative energy balance conditions 2weeks medium chain triacylglycerols [71] +MCToftotal7malesand14 (eliminating the possibility of de novo (MCT) females lipogenesis and reservation of glycogen reserves had occurred; thus, the only possible remaining mechanism increased hepatic fatty acid oxidation) No significant differences in body weight reduction, EE, appetite ratings, and Normal-moderately obese, 500 mg HCA; 500 mg HCA + 3 g substrates oxidation (protein, fat, and 2weeks groups:placebo,HCA,andHCA medium chain triacylglycerols [41] carbohydrate oxidation) within all groups +MCToftotal11male (MCT) ∗∗ Comment: 2-week intervention is too short Normal-moderately obese, No significant difference in RQ, EE, and groups: placebo, HCA of total 10 2weeks 3g(−)-HCA daily blood parameters during rest nor during [42] sedentary males, with or without exercise moderately intense exercise 1500 mg G. cambogia +300𝜇g No significant difference in control and 8 weeks 39 subjects [72] chromium picolinate/day placebo No clinically significant differences in Overweight, groups: treatment: body composition, plasma lipid profiles, 10 weeks 2gG. cambogia extract daily [73] 29; placebo: 29 antioxidant enzyme activity, and plasma adipocytokines G. cambogia extract: 3000 mg of Obese, treatment: 5 M, 61 F; No significant difference in body weight 12 week (50% of HCA); [40] placebo: 14 M, 55 F and fat mass loss Diet: 5020 kJ/day (1200 kcal/day) No difference between placebo and treatment group but significant change of the body composition improvement Obese,groups:treatment:36F, Botanical extract (1000 mg HCA 12 weeks index, body free fat mass, weight, BMI, [74] 11 M; placebo: 41 F, 10 M daily) and some other anthropometric measurements in both treatment and placebo groups No significantvariation in body 2.4 g G. cambogia (52.4% HCA) Obese,groups:treatment:25F, weight/other anthropometric and 12 weeks +1.5gA. konjac (94.9% [75] 7M;placebo:21F,5M. calorimetric parameters but significant glucomannan) hypercholesterolemic BMI 28, groups: placebo: 23; 1,667.3 mg of G. cambogia 12 weeks No significant effect76 [ ] treatment: 21 extract/day (1,000 mg HCA/day)

that the mixture exerted antiobesity effect via modulation of 6. Human Clinical Trials the metabolic derangement induced by HFD during which interactions between the multiple genes implicated in the The antiobesity effects of G. cambogia in terms of promoting process of adipogenesis might be involved, rather than simply weight loss and lowering cholesterol level were extensively suppressing appetite. A similar observation was obtained by studied. However, evidence for the effectiveness of G. cambo- Kim et al. [38], where in addition to the reduction of food gia or its derivative products was largely derived from animal intake, the food efficiency ratio (FER) was also significantly studies [126]. Despite the intriguing evidence of antiobesity lower in the G. cambogia diet administrated group than in effects of G. cambogia from in vitro and animal studies, the HFD mice, implying less efficient transformation of the more equivocal results were obtained from randomized feed mass into body mass. double-blind placebo-controlled experiments dealing with Evidence-Based Complementary and Alternative Medicine 11

Table 5: Commercialized dietary supplements that contain G. cambogia extract/HCA.

Concentration of Doses recommended Product name Company Formulation of supplement HCA (daily) 3capsulesperserving:G. cambogia extract 1500 mg 60% (−)-HCA in its 3capsules,3times (providing 900 mg of HCA), calcium 150 mg, potassium Super CitriMax Inter health free form, 1.0% daily, 30–60 min 225 mg, 0.5% sodium, 0.1% magnesium, 0.03% iron, 0.05% HCA-600-SXS N.I. (−)-HCA in its before meal total phytosterols, 0.3% total protein, 4.5% moisture, and lactone form 8.5% soluble dietary fiber Sabinsa 500 mg of GarCitrin (providing 250 mg of HCA) and 5% GarCitrin 50% (−)-HCA 500 mg, 3 times daily Corporation Garcinol 4capsulesperserving:G. cambogia 1000 mg (providing 500 mg of HCA), green tea extract 500 mg (98% 4capsules,2-3times polyphenols) (45% epigallocatechin/EGCG), guarana Sci-Fit Pro Cut 50% (−)-HCA daily, 30–60 min extract 910 mg (22% caffeine), caffeine 100 mg, L-carnitine before meal 100 mg, white willow bark extract 100 mg (standardized for 15% salicin), dandelion 100 mg, juniper berry extract 100 mg, buchu extract 100 mg, and chromium 200 mg G. cambogia and 1capsule,3times Kola Nut TerraVita — 225 mg G. cambogia fruit, 225 mg kola nut daily, with meals 450 mg 500 mg G. cambogia (providing min. 250 mg of HCA), ProThera, 1–6 capsules daily, G. cambogia 50% (−)-HCA vegetarian capsule (hydroxypropyl methylcellulose, Inc. before meals. water), cellulose, magnesium stearate, and silicon dioxide Chromium 166 𝜇g(asCrpicolinate500mgandCr G. cambogia 2capsules,3times arginate 160 mg), G. cambogia 340 mg (providing 170 mg Atrium Inc 50% (−)-HCA Plus daily of HCA), atractylodes 80 mg, citrus aurantii 80 mg, gelatin, rice powder, and magnesium staerate G. cambogia 500 mg, vitamin B5 (calcium pantothenate) 6mg, vitamin C (ascorbic acid) 5 mg, manganese G. cambogia 3capsulesdaily, BioCare Ltd. 50% (−)-HCA gluconate(providing 270 𝜇g elemental manganese) 2.5 mg, Plus 20 min before food and chromium polynicotinate 0.9 mg (providing 100 𝜇g elemental chromium) Chromium (as chromiumpolynicotinate [ChromeMate] Source 1tablet,twicedaily,1 Garcinia 1000 50% (−)-HCA and chromium picolinate) 150 𝜇g, sodium 25 mg, G. Naturals hour before meal cambogia fruit extract (providing 500 mg of HCA) 1 g Garcinia 1000 G. cambogia rind concentrate (providing 500 mg of HCA) hydroxycitric Nature’s life 50% (−)-HCA — 1 g, cellulose, silicon dioxide, magnesium stearate and acid “Micro-Cellulose”coating Natural 1capsule,2times Citrin — G. cambogia 495 mg, BioPerine 5 mg Nirvana daily Tamarind fruit extract, microcrystalline cellulose, 1-2 tablets, 3 times HCA 450 mg Higher 450 mg HCA per magnesium stearate (vegetarian source), hydroxypropyl daily, 30 min before tablet nature tablet methylcellulose coating, silicon dioxide, and acacia meal powder Viridian G. cambogia (providing 250 mg HCA) 500 mg, viridian HCA Hydroxy 1capsule,3times Nutrition 50% (−)-HCA bilberry extract, alfalfa, spirulina blend 150 mg, and citric acid daily, before meal Ltd. vegetarian cellulose capsule 120 mg 1capsule,3times HCA Life daily, 45 min before hydroxycitric Extension 50% (−)-HCA G. cambogia (fruit) (providing 250 mg of HCA) 500 mg meals with 1 capsule acid Foundation of CitriChrome G. cambogia fruit powdered extract (providing 250 mg 1 capsule, 30–60 min Hydroxycitrate Solgar 50%(−)-HCA [50%] HCA) 500 mg, hydroxypropylmethyl cellulose, before meal vegetable magnesium stearate, and silicon dioxide Garcinia fruit extract (G. cambogia)500mg,L-carnitine 1tablet,3timesdaily, 100 mg, niacin (as niacinamide) 50 mg, pantothenic acid Hydroxycitrate Metagenics — 30–60 min before (as D-calcium pantothenate) 25 mg, riboflavin 10 mg, Plus meal manganese (as manganese arginine) 750 𝜇g, and chromium (as chromium nicotinate glycinate) 75 𝜇g 12 Evidence-Based Complementary and Alternative Medicine human subjects [127–130]. Hayamizu et al. [59]conducted 6,770,782, 6,706,899, 6,676,977, 6,610,277, 6,565,847, a crossover design randomized controlled trials (RCTs) to 6,541,026, 6,489,492, 6,485,710, 6,476,071, 6,447,807, determine the “no observed adverse effect level (NOAEL)” 6,428,806, 6,426,077, 6,413,545, 6,399,089, 6,395,296, of G. cambogia extract in 44 healthy volunteers (22 males 6,277,396, 6,221,901, 6,217,898, 6,160,172, 6,147,228, 6,113,949, and 22 females) and concluded that G. cambogia is generally 6,054,128, 5,972,357, 5,911,992, 5,783,603, 5,656,314, 5,612,039, safe to be consumed. Several equivocal findings of RCTs 5,536,516, 4,007,208, 4,006,166, 4,005,086, 7,119,110, 3,994,927, were reported on the effectiveness of supplements containing 3,993,668, 7,153,877, 3,993,667, 4,028,397, 7,153,528, 7,015,250, HCA (Table 3). Some studies reported that HCA exerted no 6,638,542, 6,579,866, 6,482,858, 6,441,041, 6,383,482, significant effects as compared to the placebo group [40, 42, 6,207,714, 5,817,329, 5,626,849, and 3,965,121. 70](Table 4). All the above findings were in agreement with themostrecentmeta-analysisofRCTswhichrevealedthatG. cambogia extract possessed limited or no effects on weight- 8. Conclusions loss in human subjects [131]. Moreover, this study showed no The nutraceutical industry is flourishing, and interest in effectonsatietyorcalorieintakeinoverweightindividuals establishing scientific credibility has attained importance for consuming their habitual diet, which is in agreement with many companies and scientists. In the recent years, more past studies [41, 60, 75]. However, such comparisons must be clinical trials had been conducted to elucidate the functional made with caution as the variations in the formulations, doses effects of Garcinia/HCA supplementation on promoting administered, RCTs designs, and study populations might human health. A multitude of metabolic functions had been contribute to the discrepancy of the results. reported for HCA or HCA-containing Garcinia extract, such Preclinical studies using rodent models have confirmed as reducing blood lipids, inducing weight loss, suppressing the body weight reduction, appetite suppression, and subse- appetite, and reducing food intake based on results obtained quently food intake reduction effects of HCA in rats. Clin- in both animal trials and human clinical trials (Figure 1). ically, however, HCA failed to perform well. Several factors These discoveries make the development of evidence-based thatmightcontributetothisscenarioaretheATPcitratelyase adjuvant modalities to curb the trend of the increasing which might be important only at very high carbohydrate prevalence of obesity and obesity-related comorbidity and diets, a type of diet that most studies did not prescribe. mortality possible. We have previously reviewed and con- Besides, a high-fiber diet can bind to HCA and block it, cluded that Garcinia extract and HCA were generally safe thus reducing its efficacy. HCA and G. cambogia exerted to be consumed. Collective results from 17 clinical studies potential effects in weight management, but clinical studies which involved 873 subjects demonstrated the safety of HCA have yet to prove optimum conditions for HCA to be effective. and HCA-SX for human consumption [43]. These studies For instance, Sullivan et al. [85] reported that hepatic lipid provided scientific evidence that intake of HCA and HCA-SX synthesis was reduced only if HCA was administered before alone did not produce adverse effects and a dietary dosage of the beginning of feeding, reaching optimum 30–60 minutes up to 2800 mg/day was regarded as the “no observed adverse prior to feeding. The reason for this remains unknown. effect level (NOAEL)” of HCA-SX in human [84]. Based on these animal and human safety data, HCA-SX also received 7. Patents and Commercialization self-affirmedGRASstatusintheUSAbytheBurdockGroup in year 2003 [132]. However, definitive conclusions that The claims on enhanced human health associated with Garcinia/HCA supplements are efficient tools against various Garcinia/HCAhadbeenreviewedinSection 4.Inparticular, health problems especially obesity remain to be proven in the antiobesity effects of Garcinia/HCA were extensively larger-scale and longer-term clinical trials, despite substantial reported. This has resulted in the availability of numerous public interest in such supplements. Many diet supplements commercialized weight-management products derived from containing Garcinia/HCA marketed as weight management Garcinia/HCA (Table 5). Several products of G. cambogia products are the combination of active ingredients rather or its derivatives had been patented and commercialized. than containing a single agent. Thus it is difficult to evaluate As of August 2012, a total of 66 patents that apply to G. the effectiveness of single agents when the combination cambogia or HCA derived from Garcinia were filed with the products are tested. In addition, awareness of the safety and US Patent and Trademark Office (USPTO) since 1976 (search efficacy of the weight management supplements available in of US Patents and Trademark Office in year 2012 using themarketshouldberaisedamonghealthcareprovidersin Google patent search). These patents are on various aspects, order to assist their patients in analyzing the risks and benefits including HCA enrichment from Garcinia rind, HCA and of the dietary supplements. Thus, scientific investigations on food products/dietary supplements prepared therefrom, the potential health promoting effects of herbal preparations methods of production, and their use. The majority of the as diet supplement are prerequisites for new discoveries of patents are related to G. cambogia/atroviridis and/or HCA alternative therapies. derived from Garcinia on obesity and weight loss. The patent numbers are as follows: 8,197,867, 8,097,286, 8,017,147, 8,003,138, 7,943,186, 7,943,183, 7,927,636, 7,858,128, 7,846,970, Acknowledgment 7,772,428, 7,741,370, 7,687,082, 7,550,161, 7,507,421, 7,431,951, 7,335,651, 7,311,929, 7,230,131, 7,214,823, 7,208,615, 7,189,416, The authors would like to thanks Professor S. G. Tan for the 7,179,488, 7,063,861, 6,982,098, 6,899,891, 6,875,891, 6,855,358, proofreading of this paper. Evidence-Based Complementary and Alternative Medicine 13

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